Lamivudine (I) (CAS No. 134678-17-4) is chemically known as (2R-cis)-4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone, also known as (−) cis-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one

Lamivudine is a reverse transcriptase inhibitor used in the treatment of HIV infection alone or in combination with other class of Anti HIV drugs.
Lamivudine is commercially available in a pharmaceutical composition under the brand name EPIVIR® marketed by GlaxoSmithKine and is covered under U.S. Pat. No. 5,047,407.
U.S. Pat. No. 5,047,407 claims 1,3-oxathiolane derivatives, their geometric and optical isomers and mixtures thereof. The patent also discloses the preparation of cis and trans isomers of 2,5 substituted 1,3-oxathiolane derivatives.
U.S. Pat. No. 5,905,082 describes two polymorphic modifications of Lamivudine viz form I and II. Form 1 crystals are short rods or long thin needles with orthorhombic crystal system. Form 1 is a hydrate of Lamivudine consisting of one molecule of water per five molecules of Lamivudine. This form melts at 146° C. (Journal of Chem. Soc., Perkin Trans. 2, page 2655 (1997)). The DSC thermogram (the rate of heating: 2° C./min) of this form shows first an endotherm at 123.6° C. followed by an exotherm at 128° C., finally another endotherm at 179.6° C. This second endotherm is due to conversion of crystal form I to form II, hence form 1 is a metastable crystalline form.
However with rate of heating of 100° C./min form I shows a single endotherm at 146° C., which is it's melting point. The TGA shows a single step sharp weight loss of 2%.
Form I as per U.S. Pat. No. 5,905,082 is prepared by heating a suspension of 64.8 gm Lamivudine in 200 ml water at 45° C. to give a solution and cooling the solution to 30° C. The product crystallizes out as an unstirrable mass. Further breaking this mass and cooling it to 10° C. with stirring and thereafter filtering and drying at 45° C. for 24 hours gives form I crystals.
Form II crystals as disclosed in U.S. Pat. No. 5,905,082 are bipyramidal in shape with tetragonal crystal system. It is an anhydrous form of Lamivudine. This form melts at 177° C. (Journal of Chem. Soc., Perkin Trans. 2, page 2655 (1997)). The DSC thermogram of this form at all scan speeds shows a single peak of endotherm at 177° C. Form II is a stable crystalline form of Lamivudine and is claimed in U.S. Pat. No. 5,905,082.
Form II as per U.S. Pat. No. 5,905,082 is prepared by following procedure: Heat a suspension of 10 gm Lamivudine in 200 ml of industrial methylated spirit to reflux to obtain a clear solution. Filter the solution while hot; distil half the amount of the solvent from the filtrate then stop heating and seed the concentrated solution with authentic form II crystals. The seeded solution is then cooled from 80° C. to 25° C. during one hour. Crystal formation starts at 79° C. Further cooling the suspension to 15° C. and stirring for an hour, filtration, washing with IMS and drying gives Form II crystals.
Crystalline form I have inferior flow property and also lower bulk density, which create problem in handling the product during formulation. In view of the literature cited hereinbefore Lamivudine form I also suffers from stability issues. Therefore, it is desirable to develop a crystalline form of Lamivudine having improved stability and also comparable if not better bioavailability.
When slurried in water both crystal form I and II get converted to another polymorphic form not yet reported in the literature, which is really not a desirable feature for manufacturing practices. Form I converts to form II during milling and formulation operation and because of this the invention embodied in U.S. Pat. No. 5,905,082 for getting form II, a thermodynamically stable polymorph, used for formulation.
The present inventors have surprisingly i found that Lamivudine can also be obtained in a third crystalline form (hereinafter form III), which not only have distinct powder X-ray diffractogram but also have entirely different single crystal X-ray diffraction when compared to form I and II.